Stem cells are a type of cell that could be a source for the replacement of damaged or diseased tissues. Embryonic stem cells (ESCs) are a type of stem cells that are attracting particular interest. The unique characteristics of ESCs include their capacity to regenerate themselves and develop into various cell types of all three embryonic germ layers, i.e., ectoderm, mesoderm and endoderm, under appropriate conditions. Such differentiated cell types include, but are not limited to, muscle, nerve, heart, liver, bone and blood. The potential of ESCs, induced pluripotent stem cells (iPSCs), adult or tissue specific stem cells and the like to grow into specialized cells has attracted interest for research and disease treatment using these cells. The clinical application of stem cells involves harvesting of these cells and transplantation of the cells into individuals with failing organs in order to restore the function of the organs with or without prior in vitro differentiation. Another application involves differentiating large quantities of stem cells into particular human cell types in a biotechnology sense and using these cells for pharmaceutical drug testing or toxicity testing.
Emerging evidence suggests that the Wnt signaling pathway regulates crucial aspects of cardiac morphogenesis and self-renewal and differentiation of cardiac progenitor cells. Stem cell differentiation is a complex process that appears to have a temporal role in cardiovascular development as shown by Keller and Yang (Yang et al., Nature, 2008, 453, p. 524-528). The activity of the Wnt/β-catenin signaling pathway is dependent on the amount of β-catenin in the cytoplasm. Normally, cytoplasmic β-catenin is maintained at a low level through degradation that is regulated by a multiprotein “destruction” complex containing Axin. Upon Wnt stimulation, Axin translocates to the cell membrane to interact with LRP5 and Dvl. Dvl becomes phosphorylated and subsequently inhibits GSK3β phosphorylation of β-catenin thereby resulting in the accumulation of non-phosphorylated β-catenin in the cytoplasm. Non-phosphorylated β-catenin avoids degradation and translocates into the nucleus. Upon entering the nucleus, β-catenin binds to the transcription factors Tcf/LEF that promotes the expression of Tcf-regulated genes. Binding to Tcf/LEF is enabled by the presence of coactivators (CBP and/or P300). Accordingly, identification of compounds and methods for modulating and/or inhibiting Wnt pathways may offer an avenue for stem cell differentiation including the production of cardiomyocytes and for the therapeutic treatment of diseases including cancer and other proliferative diseases associated with this pathway.